Chronic fluoxetine upregulates activity, protein and mRNA levels of cytosolic phospholipase A2 in rat frontal cortex

Abstract

Chronic lithium and carbamazepine, which are effective against mania in bipolar disorder, decrease the activity of cytosolic phospholipase A 2 (cPLA 2 ) and the turnover rate of arachidonic acid in phospholipids in rat brain. Assuming that stages of bipolar disorder are related to brain arachidonic acid metabolism, we hypothesized that drugs effective in depression would increase cPLA 2 activity. To test this hypothesis, adult male CDF-344 rats were administered fluoxetine (10 mg/kg intraperitoneally (i.p.) or saline (control) (i.p.) chronically for 21 days. Frontal cortex cPLA 2 protein, phosphorylated cPLA 2 , activity and mRNA levels were increased after chronic fluoxetine. Transcription factors (activator protein-1, activator protein-2, glucocorticoid response element, polyoma enhancer element-3 and nuclear factor-kappa B ) that are known to regulate cPLA 2 gene expression were not significantly changed by chronic fluoxetine, but nuclear AU-rich element/poly(U)-binding/degradation factor-1 RNA-stabilizing protein was increased significantly. The results suggest that chronic fluoxetine increases brain cPLA 2 gene expression post-transcriptionally by increasing cPLA 2 mRNA stabilization. Chronic fluoxetine's effect on cPLA 2 expression was opposite to the effect reported with chronic lithium or carbamazepine administration, and may be part of fluoxetine's mode of action.

RETRACTED ARTICLE: Chronic fluoxetine increases cytosolic phospholipase A2 activity and arachidonic acid turnover in brain phospholipids of the unanesthetized rat

“…These findings are consistent with the short half-life of cPLA 2 mRNA (3-4 h) (Tay et al 1994) and the rapid washout of fluoxetine and norfluoxetine from rat brain (Caccia et al 1990). Chronic (but not acute) fluoxetine has been shown to increase cPLA 2 protein and mRNA in the rat frontal cortex, likely by increasing the level of AU-rich element/poly(U)-binding/degradation factor which stabilizes cPLA 2 mRNA (Rao et al 2006). The increased protein level of cPLA 2 observed in the current study is likely explained by chronic fluoxetine's ability to increase cPLA 2 mRNA.…”

Chronic treatment of astrocytes with therapeutically relevant fluoxetine concentrations enhances cPLA2 expression secondary to 5-HT2B-induced, transactivation-mediated ERK1/2 phosphorylation

“…The present observations confirm the observations by Qu et al (2006), Rao et al (2006), and Lee et al (2008) who showed fluoxetine-mediated upregulation of cPLA 2 activity and expression in intact brain by demonstrating similar cPLA 2 upregulation by fluoxetine in astrocytes, a brain cell type that constitutes about 20% in gray matter (Hertz 2008) and may be the site of most of its cPLA 2 expression (Lautens et al 1998;Balboa and Balsinde 2002;Sun et al 2004). They provide no information whether neurons may respond in a similar manner, but attempts to treat neurons chronically with fluoxetine failed, because the neuronal cultures did not tolerate the treatment well (Li and Peng, unpublished experiments).…”

“…Consistent with the results by Rao et al (2006), cPLA 2a was found to be upregulated, whereas the two other forms of PLA 2 , sPLA 2 and iPLA 2 , were unaffected. Since these cultures express no serotonin transporter (Kong et al 2002;Li and Peng, unpublished experiments) and any 5-HT present in the serum added to the culturing medium is rapidly metabolized by the high monooxidase activity in the cells Hertz 1982, 1983), the upregulation cannot be caused by inhibition of 5-HT uptake, but must be a direct effect of fluoxetine, i.e., of stimulation of 5-HT 2B receptors.…”

“…The linkage between fluoxetine-mediated ERK 1/2 phosphorylation and cPLA 2 upregulation in the cultured astrocytes is not known. On one hand, Rao et al (2006) concluded that several transcription factors known to regulate cPLA 2 gene expression were not significantly changed by chronic fluoxetine administration in the brain in vivo. However, nuclear AU-rich element/poly(U)-binding/degradation factor-1 RNA-stabilizing protein was significantly increased, suggesting that chronic fluoxetine increases brain cPLA 2 gene expression post-transcriptionally by increasing stabilization of cPLA 2 mRNA.…”

“…During chronic administration of an SSRI, the 5-HT levels in the brain become increased, at least in most regions (Beyer and Cremers 2008), long before amelioration of mood (Nierenberg et al 2000), suggesting that changes in signaling in response to either the increased extracellular 5-HT concentration, or perhaps even the SSRI itself, are required for therapeutic effectiveness. In an attempt to clarify such mechanisms, Rapoport and coworkers (Qu et al 2006;Rao et al 2006;Lee et al 2008) recently showed that chronic administration of fluoxetine (10 mg/kg/day) for 21 days leads to stimulation and enhanced mRNA and protein expression of Ca 2+ -dependent phospholipase A 2 (cPLA 2 ) in the rat brain, but not of the two other phospholipases A 2 (secretory PLA 2 [sPLA 2 ] and intracellular PLA 2 [iPLA 2 ]). After stimulation of one of several different neurotransmitter receptors, including 5-HT 2A/2C receptors, cPLA 2 releases arachidonic acid from the sn-2 position of membrane-bound phospholipid substrate in neural preparations (Felder et al 1990;Stout et al 2002;Qu et al 2003;Rapoport 2008), including glioma cells (Garcia and Kim 1997).…”